Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
Int J Mol Sci. 2022 May 14;23(10):5490. doi: 10.3390/ijms23105490.
Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP-Epac-CREB signaling pathway to upregulate FGF21 expression in hepatocytes.
成纤维细胞生长因子 21（FGF21）作为一种调节葡萄糖和脂质代谢的多肽激素发挥作用，其表达受细胞代谢应激的调节。丙酮酸是一种重要的中间代谢物，作为细胞燃料代谢的关键枢纽。然而，丙酮酸对肝 FGF21 表达和分泌的影响尚不清楚。在此，我们在体外检查了人肝癌 HepG2 细胞和鼠 AML12 肝细胞以及体内小鼠中 FGF21 的基因表达和蛋白水平。在 HepG2 和 AML12 细胞中，浓度高于 0.1mM 的丙酮酸显著增加了 FGF21 的表达和分泌。通过激活腺苷酸环化酶、抑制磷酸二酯酶（PDE）和给予 8-溴-cAMP，细胞内 cAMP 水平的增加显著抑制了丙酮酸刺激的 FGF21 表达。丙酮酸显著增加了 PDE 活性，降低了 cAMP 水平并降低了 CREB 磷酸化。cAMP 反应元件结合蛋白（CREB）和 cAMP 反应元件结合蛋白（CREB）的交换蛋白定向激活（Epac）的抑制上调了 FGF21 的表达，此时丙酮酸不再增加 FGF21 的表达。与对照组相比，丙酮酸腹腔注射诱导的小鼠血浆丙酮酸水平升高显著增加了小鼠肝脏中 FGF21 基因表达和 PDE 活性，同时降低了 cAMP 水平和 CREB 磷酸化。总之，丙酮酸激活 PDE 以降低 cAMP，然后抑制 cAMP-Epac-CREB 信号通路，从而上调肝细胞中 FGF21 的表达。
